Deciphering the functions of human exon junction complexes

• Applicants: Professor Dr. Christoph Dieterich; Professor Dr. Niels H. Gehring
• Subject Area: Cell Biology ; Bioinformatics and Theoretical Biology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418083979

• Final Report Year: 2024

Final Report Abstract

In this project, we analysed cells with reduced levels of the exon junction complex (EJC), an essential regulator of diverse processes involved in gene expression, and its associated factors (PNN, RNPS1, SAP18). Transcriptome-wide analyses of EJC and RNPS1 knockdowns suggest that RNPS1 moderately influences nonsense mediated mRNA decay (NMD), a cellular quality control process, but is not essential for NMD activity. In contract, RNPS1’s main function is found to be in splicing regulation and to prevent aberrant splicing events using cryptic splice sites. Additionally, we conducted a thorough analysis of cells lacking CASC3, another EJC-associated factor, and observed its connection to the NMD machinery. This work revealed the stabilization of NMD substrates and identified specific transcripts affected by CASC3. Furthermore, our sequencing grant supported studies on samples with in inhibited NMD. The latter samples are still under active investigation.

Publications

• CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex. Nucleic Acids Research, 48(15), 8626-8644.
  Gerbracht, Jennifer V.; Boehm, Volker; Britto-Borges, Thiago; Kallabis, Sebastian; Wiederstein, JanicaL; Ciriello, Simona; Aschemeier, Dominik U.; Krüger, Marcus; Frese, Christian K.; Altmüller, Janine; Dieterich, Christoph & Gehring, NielsH
  
• SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity. Nature Communications, 12(1).
  Boehm, Volker; Kueckelmann, Sabrina; Gerbracht, Jennifer V.; Kallabis, Sebastian; Britto-Borges, Thiago; Altmüller, Janine; Krüger, Marcus; Dieterich, Christoph & Gehring, Niels H.
  
• Exon junction complex-associated multi-adapter RNPS1 nucleates splicing regulatory complexes to maintain transcriptome surveillance. Nucleic Acids Research, 50(10), 5899-5918.
  Schlautmann, Lena P.; Lackmann, Jan-Wilm; Altmüller, Janine; Dieterich, Christoph; Boehm, Volker & Gehring, NielsH
  
• Human UPF3A and UPF3B enable fault‐tolerant activation of nonsense‐mediated mRNA decay. The EMBO Journal, 41(10).
  Wallmeroth, Damaris; Lackmann, Jan‐Wilm; Kueckelmann, Sabrina; Altmüller, Janine; Dieterich, Christoph; Boehm, Volker & Gehring, Niels H.